Head injury is a complex disease involving two distinct patterns of injury, primary injury and secondary injury. There is significant morbidity and mortality associated with brain injury with about 50,000 deaths and 235,000 hospitalizations each year. In spite of major advancements in the understanding of the molecular mechanisms associated with secondary injury induced by traumatic brain injury (TBI), failure to discover a therapeutic agent to mitigate these affects in humans has been a persistent disappointment to researchers. Several agents have shown promise in the laboratory but have not translated into success beyond the animal model. When trials were comprehensively reviewed, inadequate statistical sensitivity, inadequate pre-clinical data and lack of drug disposition data documenting access to the brain were identified as important contributing factors. Cyclosporine A (CsA) has been shown in multiple animal models to be neuroprotective by attenuating mitochondrial dysfunction and preventing axonal destruction thus improving outcomes. Animal studies have shown that a continuous infusion preceded by a bolus dose given within 12 hours of injury maximizes CsA protective effects. In addition, our early clinical trial investigations of CsA in severe TBI have shown that the drug is safe, that higher continuous infusion doses are more effective, that CsA is detected in the central nervous system, and that CsA treated patients have a trend toward better outcomes. This planning grant proposal is necessary to complete the steps required for the initiation of a Phase III multi-center clinical trial in severe TBI patients evaluating CsA therapy (CASTBI). A double-blind, placebo controlled trial of 1218 patients investigating CsA will be designed to test the hypothesis that patients suffering from a severe TBI treated with a continuous infusion of CsA for three days will have an improved functional outcome compared to placebo. The primary endpoint assessment of functional outcome will be the Glasgow Outcome Scale at 6 months. This planning grant period will be used to: (1) identify executive committee and sub-committee members; (2) finalize study documents including protocol, manual of operations, case report forms, and investigational new drug application; (3) recruit study sites; (4) prepare and validate the data management systems; (5) develop training and certification materials for outcome assessments; (6) organize investigator's meeting; and (7) prepare Phase III CASTBI grant for submission. [unreadable]